Biofunctional Synthesis

The first synthesis of isochromene fused carbazols, (4aS, 13bR)-2,5,5-trimethyl-3,4,4a,5,8,13b-hexahydroisochromeno[3,4-b]carbazole (2) and its epi-isomer 3 by condensation of citral and 2-hydroxycarbazole using Ti(OEt)4 and MeAlCl2 as catalysts is described.

Multiple multicomponent macrocyclizations including bifunctional buildings blocks (MiBs) so far have relied almost exclusively on Ugi reactions. The efficient expansion to non-Ugi-MiBs is exemplified by the synthesis of tetra-β-lactam and bis-α-acyloxy carboxamide macrocycles based on multiple Staudinger and Passerini three-component reactions (3CR), respectively. A recent variation of the Passerini-3CR that involves primary alcohols, isocyanides, and carboxylic acids under oxidative conditions is successfully adapted to this procedure.

The formation and 2-amino alcohol catalyzed addition of arylzinc reagents from and with boronic acids, respectively, is drastically accelerated to a few minutes under microwave irradiation without loss of enantioselectivity (up to 98% ee). Of the amino acid derived catalysts tested, the conformationally restricted bulky substituted aziridine-2-methanols derived from serine show the best overall performance in the formation of diarylmethanols.

A small parallel library of peptoid macrocycles with natural-product-derived side chains of biological importance was produced by Ugi-type multiple multicomponent macrocyclizations including bifunctional building blocks (Ugi-MiBs). Diverse exocyclic elements of high relevance in natural recognition processes, i.e., all functional amino acid residues (e.g., Cys, Arg, His, Trp) and even sugar moieties, can be introduced in a one-pot process into different types of peptoid-containing macrocyclic skeletons. This is exemplified by the use of a diamine/diisocyanide combination of Ugi-MiBs and N-protected α-amino acids or carboxy-functionalized carbohydrates as source for the natural-product-like exocyclic elements. Employed as the acid components of the multiple Ugi reactions, they appear as N-amide substituents on the macrocyclic cores. The use of different diamines and diisocyanides allows an easy variation of the N- to C-directionality and therefore of the position of the exocyclic elements.

Bile acids are important scaffolds in medicinal and supramolecular chemistry. However, the use of seco bile acids, i.e., bile acids with opened rings, as cores or building blocks for the assembly of complex peptide conjugates or macrocycles has remained elusive so far. A biomimetic approach to secocholanes, based on an oxidative ring-expansion/ring-opening sequence, offers efficient access to novel structures with tunable flexibility and functionality. The process preserves selected portions of the original stereochemical and functional information of the steroid, while additional structural elements are incorporated in further (diversity-generating) steps. The potential of these building blocks for peptide and macrocycle chemistry is exemplified by the attachment of relevant α-amino acids and by the production of various complex macrocycles obtained by conventional (e.g., macrolactonization and macrolactamization) and multicomponent (e.g., Ugi four-component) macrocyclizations. This combination of secocholanic skeleton manipulation with, e.g., varied types of macrocyclization protocols, produces high levels of skeletal diversity and complexity. Therefore, this approach may have applicability either for the synthesis of biologically active ligands or as artificial receptors (“hosts”).

A new strategy for the synthesis of cyclic peptoids was developed. The approach is based on the use of consecutive Ugi reactions for the assembly of the acyclic peptoid and for the ring closure. Cyclopentapeptoid analogues of the RGD peptides were designed and synthesized using this methodology. The results confirm the versatility and efficiency of the method for the preparation of cyclic oligopeptoids.

A short survey of historic and current methods for the synthesis of selenocysteine, selenocystine, and derivatives and related compounds is presented, with an additional emphasis on the formation of selenocysteine‐derived SeS bridges. The majority of methods to the amino acid starts with protected and O ‐activated serine, but also other concepts are included such as radical or multicomponent strategies, the latter allowing also direct access to peptoids in one pot. Of special importance is the monomeric oxidative cyclization of selenocysteine–cysteine peptides to eight‐membered and larger rings with a selenenylsulfide bridge, a crucial element in several selenoproteins.

Takai–Utimoto reactions with secondary and tertiary aliphatic halides usually failed according to previous reports. Now, significant improvements could be achieved, and especially secondary aliphatic halides can be coupled to aromatic aldehydes in yields of up to >95%. A variety of processes are competing with the desired one, and thus conditions must be adapted to the nature of the aldehyde as well as the aliphatic halide used, as the outcome of these reactions is strongly affected by the putative radical intermediates.

In alcohols and esters, a neighbouring dialkylamino group can enhance the reactivity towards acylation and deacylation, respectively, that is, such amino alcohols can act as transacylation catalysts like DMAP. This effect is dependent on the number of (carbon) spacer atoms, flexibility of the molecule and the presence and position of further heteroatoms. Based on this effect, the site selective acylation and deacylation of desmycosin, a macrocycle antibiotic possessing an amino sugar moiety, is described.

A simple, rapid, one-pot multicomponent synthesis of tryptophan-derived diketopiperazines with variable side chains is presented. Microwave radiation gives comparable yields, but allows a significant decrease in reaction times.